Design, Synthesis, and Biological Characterization of Orally Active 17β-Hydroxysteroid Dehydrogenase Type 2 Inhibitors Targeting the Prevention of Osteoporosis.

Osteoporosis is predominantly treated with drugs that inhibit further bone resorption due to estrogen deficiency. Yet, osteoporosis drugs that not only inhibit bone resorption but also stimulate bone formation, such as potentially inhibitors of 17/3-hydroxysteroid dehydrogenase type 2 (17/3-beta HSD2), may be more efficacious in the treatment of osteoporosis. Blockade of 17 beta-HSD2 is thought to increase intracellular estradiol and testosterone in bone, thereby inhibiting bone resorption by osteoclasts and stimulating bone formation by osteoblasts, respectively. We here describe the design, synthesis, and biological characterization of a novel bicyclic-substituted hydroxyphenylmethanone 17 beta-HSD2 inhibitor (compound 24). Compound 24 is a nanomolar potent inhibitor of human 17 beta-HSD2 (ICso of 6.1 nM) and rodent 17P-HSD2 with low in vitro cellular toxicity, devoid of detectable estrogen receptor a affinity, displays high aqueous solubility and in vitro metabolic stability, and has an excellent oral pharmacokinetic profile for testing in a rat osteoporosis model. Administration of 24 in a rat osteoporosis model demonstrates its bone-sparing efficacy.